The ability of hepatic stem/progenitor cells to respond to severe liver injury is dependent upon a finely tuned balance of progenitor cell renewal, expansion and differentiation. In the liver, developmentally activated signaling pathways including the hedgehog, wnt and notch systems have been implicated in the regulation of hepatic progenitor cell renewal, tissue repair and the development of hepatocellular cancer. Until now, lack of specific genetic tools to modulate these pathways in adult hepatic progenitors has precluded the analysis of the specific contribution of these pathways to the progenitor cell response to liver injury. We have discovered that the winged helix transcription factor Foxl1 uniquely marks bipotential hepatic progenitor cells and have derived both Foxl1-Cre and tamoxifen inducible Foxl1-CreERT2 mouse strains to enable gain- and loss-of-function studies through the conditional deletion of individual components of the hedgehog, wnt and notch signaling pathways in hepatic progenitor cells. Using this approach, we will dissect the complex autocrine and paracrine signaling events that contribute to progenitor cell recruitment, differentiation and proliferation as well as paracrine effects on fibrogenesis during tissue repair in response to liver injury. We propose the existence of a signaling hierarchy in which the winged helix factor Foxl1 mediates the hedgehog and wnt/b-catenin signaling pathways necessary for progenitor cell renewal and proliferation. We predict that Notch acts downstream of wnt/b-catenin and promotes progenitor cell differentiation towards the biliary lineage and may also be required for biliary tubule morphogenesis. Understanding the biology of hepatic progenitor cells will have wide-ranging implications for the development of therapeutics for acute liver failure, chronic cirrhotic liver disease and hepatocellular carcinoma. PUBLIC HEALTH RELEVANCE: The studies proposed in this grant application will elucidate the signals that regulate hepatic progenitor cells and their response to acute or chronic liver injury. Understanding the biology of hepatic progenitor cells will have wide-ranging implications for the development of therapeutics for acute liver failure, chronic cirrhotic liver disease and hepatocellular carcinoma.